Our long term objective is to understand the degree and duration of protection induced by HIV drug early treatment effects on malaria infection (infection-treatment-vaccination or ITV), and the role of ITV in naturally acquired immunity. Attenuated malaria parasites that arrest during liver stage development confer complete protective immunity in animals and humans. Similar immunity is observed in mice that are infected with wild-type parasites and then given primaquine, a drug with causal prophylaxis effect (cidal liver stage effect). Protective immunity is also observed in humans or mice that are infected with wild-type parasites while receiving chloroquine, a drug with suppressive prophylaxis effect (suppressive blood stage effect). Taken together, the data indicate that antimalarial treatment early during malaria infection (or ITV) can induce highly effective immunity. Presumably, many drug regimens with antimalarial activity might contribute to an ITV effect. We hypothesize that: 1) early treatment of rodent malaria infection with HIV drugs that have causal prophylaxis effects can induce protective immunity against liver stage parasites; and 2) the use of HIV drugs with causal prophylaxis effects may contribute to naturally acquired protective immunity in African children. Using rodent models of malaria, we show that certain HIV drugs are also able to kill LS parasites, and that ITV with HIV drugs can induce the development of protective immunity against liver stage parasites. These are important findings given the malaria-HIV co-epidemic in Sub-Saharan Africa. In parallel, we are collecting data from field trials to examine whether use of HIV drugs with causal prophylaxis effects may contribute to naturally acquired protective immunity in African children. RESEARCH DESIGN AND METHODS. Specific Aim 1, Rodent Experiments: Experiments will be based upon published regimens in which mice infected with Plasmodium yoelii treated with causal or suppressive prophylaxis develop protective immunity when challenged. P. yoelii infection in mice also has strong precedent in malaria vaccine research, as P. yoelii better models the infectivity of the human malaria parasite P. falciparum. Experiments will be undertaken in Swiss Webster (outbred) mice as outbred mice will more accurately reflect the genetic diversity of human populations. Briefly, mice will be immunized with regimens known to confer protective immunity compared to mice treated with a variety of drugs administered during the LS and BS. For regimens that induce protection, assessment of degree and duration of immunity will follow: differential immunization and challenge regimens will be used, including challenge with increasing numbers of sporozoites via tail vein infection to assess the magnitude of protection as proof of concept. Mosquito bite challenge will then be assessed to simulate field conditions. Challenges will also be conducted with infected red blood cells to assess development of cross-stage specific immunity (important for breakthrough BS infection, as cross-stage specific immunity may offer protection if the LS-cidal drug fails to eliminate all LS parasites). Challenge will be assessed using different species (P. berghei) to assess cross-species protection. Within the context of these regimens, mice will be immunized and challenged at differing time intervals to assess the duration of immunity, which will bear direct relevance to subsequent field studies. Specific Aim 2, Field Assessment of Protective Immunity Against Liver Stage Parasites: Use of and compliance with antimalarial and HIV drugs will be monitored in a longitudinal cohort. These factors will be related to the development of malaria resistance, that is, evidence of LS parasite exposure in patients who do not develop BS infection. Adjustment for other factors contributing to malaria resistance, such as iron deficiency, insecticide treated net use, immunologic status (patient age and HIV status), malaria-resistance genes, and vector exposure, will be taken into account.